Abstract IA28: PI3K and mTOR inhibitors in lymphoid malignancies: Clinical data

Abstract

Abstract Activation of pathways associated with PI3 Kinase and mTOR is commonly associated with a variety of lymphoid cancers, and can result in cell survival, growth and resistance to standard chemoimmunotherapeutics. Strong preclinical rationale has led to several agents that have been evaluated in clinical trials, both as monotherapy and in combination strategies. The mTOR inhibitors everolimus Iand temsirolimus have demonstrated clear clinical activity and acceptable toxicity profiles in patients with a variety of lymphoid malignancies. Temsirolimus has been approved in the European Union and several other countries outside of the US for the treatment of relapsed and/or refractory mantle cell lymphoma. This approval was based on a phase 3 randomized trial comparing temsirolimus at 2 dosing levels vs. investigator's therapy choice, which demonstrated an improvement in progression-free survival and overall response rate. Single agent activity of temsirolimus has also been demonstrated in other lymphoma subtypes such as diffuse large B cell and follicular lymphoma, and combination studies have been performed with rituximab. Everolimus has also been evaluated in mantle cell, diffuse large B cell and follicular lymphoma, as well as Hodgkin lymphoma, and clinical activity has also been noted. Combination studies with histone deacetylase inhibitors, rituximab and lenalidomide are underway. To date, activity of PI3K inhibitors appears to be most significant in lymphoid malignancies. Idelalisib, an inhibitor of the PI3K delta isoform, is FDA approved as a single agent for patients with follicular lymphoma and small lymphocytic lymphoma, and in combination with rituximab for recurrent chronic lymphocytic leukemia. Responses have been noted in mantle cell lymphoma, though durability is short. Numerous combination studies with chemotherapy and rituximab are ongoing. IPI-145 is an oral inhibitor of the delta and gamma isoforms of PI3K, and early studies have shown activity in both indolent B cell lymphomas as well as T cell histologies. The alpha and delta PI3K inhibitor copanlisib has also demonstrated early activity in a range of lymphoid histologies. The clinical activity and toxicity profile of PI3K inhibitors has suggested a significant potential role for these agents in the treatment of various lymphoproliferative cancers. Ongoing studies are evaluating potential biomarkers for response and resistance, as well as the development of rational combination approaches. Clinical findings suggest at this stage that targeting mTOR and PI3K represents a valuable therapeutic approach in lymphoma and that further investigation in this area will lead to further progress in improving patient outcomes. Citation Format: John P. Leonard. PI3K and mTOR inhibitors in lymphoid malignancies: Clinical data. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA28.